Stem cell scientists debate finer points of research ethics / Should egg donors be paid? When are animal studies OK?

Alex Barnum, Chronicle Staff Writer

Published 4:00 am, Sunday, June 26, 2005

For years, the debate over embryonic stem cell research in the United States was stuck on one question. Some ethicists call it the "what's-in- the-(Petri)-dish" problem: Is an embryo a life, just a mass of cells or perhaps something in between?

Where you come down on that question largely dictates how you feel about stem cell research, which requires that embryos be destroyed. The political battle lines were drawn years ago, and despite efforts at finding some middle ground, the issue remains deadlocked, at least in Washington.

But with the passage of California's stem cell initiative, and with similar but less ambitious proposals headed toward approval in a half-dozen statehouses from Connecticut to Wisconsin, the stem cell debate is shifting focus. It's no longer about whether to do it, but how to do it in an ethically appropriate way.

"Let the Capitol have its debate. It's irrelevant," said David Magnus, director of the Stanford Center for Biomedical Ethics. "It's only the Washington-centric nature of our country that anyone should care about what Congress' policy is on this. Clearly, it's going to happen, so the question is, 'How can it happen ethically?' "

-- How do we prepare for some of the inevitable disappointments after the first people enter embryonic stem cell clinical trials?

In May, the National Academies, the country's leading science advisory group, released the first comprehensive set of guidelines for conducting stem cell research, intended to both reassure the public and providing scientists with rules that will remain the same from campus to campus and state to state.

Although widely applauded by scientists and patient advocates, the guidelines are probably not the last word. Some of the rules still prompt disagreement, and many experts say that they leave some important questions unanswered.

For example, the guidelines require that both genetic donors of an embryo -- male and female -- consent to its use for stem cell research. That may seem obvious, but, in fact, many of the 22 stem cell colonies currently available for federal grants were created using anonymously donated sperm.

"Most of the existing stem cell lines don't meet the National Academies' standard. Are they going to be grandfathered in?" Magnus asked.

For newly created stem cells -- which is where the action is headed -- there are questions of compensating donors and even whether those donors constitute an entirely new type of medical research participant.

Generally speaking, there are two ways of making stem cells, which hold great medical promise because of their ability to morph into any cell type. The first approach involves extracting the cells from 5- to 7-day-old embryos, which are donated by infertile couples who would otherwise discard them.

The other way is through a process called nuclear transfer, in which the nucleus of an egg is removed and replaced with the DNA from another cell, a skin cell perhaps. The egg is tricked into developing into an embryo, and goes on to produce stem cells with all the traits of the donor of the skin cell.

Last month, South Korean researchers announced they had dramatically improved the efficiency of obtaining stem cells using this method. Earlier studies had yielded one line of stem cells for every 200 to 300 embryos. But the South Koreans' latest work improved the efficiency to about 1 in 10.

That's not only an order of magnitude improvement, it also means that a typical female donor who produces about 10 eggs in a single, artificially induced ovulation cycle can produce enough to yield one stem cell line using the technique developed by the South Koreans.

Given the expanding interest in this line of research, the stem cell donors of choice may well be individual women who donate their eggs specifically for research, not couples who donate embryos left over from fertility treatments.

But according to Magnus and his Stanford colleague Mildred Cho, writing in the same issue of Science that published results of the South Korean study, donors in that study were not properly informed about the risks of the egg collection process. "They were never told about the risk of infertility or death," Cho said.

Because egg donors' risks are substantially greater than those faced by blood or sperm donors, for example, and because they do not benefit from participation as many other medical research subjects do, Magnus and Cho argue for creating a new category of "research donors" that comes with a set of protections designed specifically for their situation.

On the question of compensation, the National Academies panel recommended that women who donate their eggs specifically for stem cell research be reimbursed for the cost of the egg collection procedure but nothing more.

But Dr. Bernard Lo, director of UCSF's Program in Medical Ethics, notes that compensation is considered acceptable for donation of certain types of tissue, such as corneas. And most research volunteers, he says, are paid for their time and inconvenience.

Moreover, he points out that women who "donate" their eggs to infertile couples can be paid as much as $30,000 or $40,000 per ovulation cycle, beyond the costs of egg extraction.

Once human stem cells have been properly obtained, they will need to be studied in animals -- raising more ethical questions.

The National Academies guidelines divide research into three categories: experiments that raise no ethical issues, those that would need approval by a special "embryonic stem cell research oversight committee," and those that would be banned outright.

In the third category, for example, is any experiment placing human stem cells into a primate embryo. Because of stem cells' ability to distribute throughout the body, including the brain, it would be conceivable to create an animal with a human or partly human mind trapped in a monkey's body.

But there may be good reasons for creating mice with human brain cells. Parkinson's and Alzheimer's diseases, for example, are characterized by the loss of certain types of brain cells. Before conducting trials in humans, scientists will want to explore how neural stem cells affect such deficits in the brains of mice.

Finally, there are host of ethical problems that will arise with the first human clinical trials.

"There's so much excitement, hope and, frankly, hype that patients are likely to be clamoring to get into the first clinical trials," said UCSF's Lo. "But we don't really know what's going to happen. People could be made worse, as with any clinical trial. It's important that people understand this is a longshot."